Interpretation of the short Synacthen test in the presence of low cortisol-binding globulin: two case reports

Ten percent of serum total cortisol (TC) is unbound; the remainder is bound to cortisol-binding globulin (CBG) and, to a lesser extent, albumin. CBG concentrations can drop significantly, particularly in critical illness, resulting in a low TC although the free, active, cortisol may be normal or increased. In the context of a low CBG, the diagnosis of pituitary-adrenal insufficiency with measurements of TC is difficult.

To remind clinicians of the difficulty in interpreting TC when the CBG is low, the circumstances when CBG concentrations may decrease and that measurement of CBG and calculation of the free cortisol index can help in the assessment of pituitary-adrenal reserve.

We present two patients at risk of primary and secondary adrenal insufficiency with a poor response to 250 microg Synacthen. In both cases we confirmed low CBG concentrations but a normal free cortisol index (FCI), confirming normal pituitary-adrenal reserve.

In case one, we have been able to avoid long-term steroid replacement therapy. We continue to reduce the steroid dose in case 2 but have been limited by the need for high-dose steroid treatment for exacerbations of the patient's airways disease.

The use of TC in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis may give rise to misleading results if the CBG concentration is low. The FCI may be a better marker of pituitary-adrenal reserve in these subjects. Clinicians should be cautious when interpreting abnormal cortisol results and we emphasize the importance of good clinical assessment.